Dataset Information

IP3R1/GRP75/VDAC1 complex mediates endoplasmic reticulum stress-mitochondrial oxidative stress in diabetic atrial remodeling.

ABSTRACT:

Rationale

Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are important mechanisms of atrial remodeling, predisposing to the development of atrial fibrillation (AF) in type 2 diabetes mellitus (T2DM). However, the molecular mechanisms underlying these processes especially their interactions have not been fully elucidated.

Objective

To explore the potential role of ER stress-mitochondrial oxidative stress in atrial remodeling and AF induction in diabetes.

Methods and results

Mouse atrial cardiomyocytes (HL-1 cells) and rats with T2DM were used as study models. Significant ER stress was observed in the diabetic rat atria. After treatment with tunicamycin (TM), an ER stress agonist, mass spectrometry (MS) identified several known ER stress and calmodulin proteins, including heat shock protein family A (HSP70) member [HSPA] 5 [GRP78]) and HSPA9 (GRP75, glucose-regulated protein 75). In situ proximity ligation assay indicated that TM led to increased protein expression of the IP3R1-GRP75-VDAC1 (inositol 1,4,5-trisphosphate receptor 1-glucose-regulated protein 75-voltage-dependent anion channel 1) complex in HL-1 cells. Small interfering RNA silencing of GRP75 in HL-1 cells and GRP75 conditional knockout in a mouse model led to impaired calcium transport from the ER to the mitochondria and alleviated mitochondrial oxidative stress and calcium overload. Moreover, GRP75 deficiency attenuated atrial remodeling and AF progression in Myh6-Cre⁺/Hspa9^flox/flox + TM mice.

Conclusions

The IP3R1-GRP75-VDAC1 complex mediates ER stress-mitochondrial oxidative stress and plays an important role in diabetic atrial remodeling.

SUBMITTER: Yuan M

PROVIDER: S-EPMC8961221 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Publications

IP3R1/GRP75/VDAC1 complex mediates endoplasmic reticulum stress-mitochondrial oxidative stress in diabetic atrial remodeling.

Yuan Ming M Gong Mengqi M He Jinli J Xie Bingxin B Zhang Zhiwei Z Meng Lei L Tse Gary G Zhao Yungang Y Bao Qiankun Q Zhang Yue Y Yuan Meng M Liu Xing X Luo Cunjin C Wang Feng F Li Guangping G Liu Tong T

Redox biology 20220321

<h4>Rationale</h4>Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are important mechanisms of atrial remodeling, predisposing to the development of atrial fibrillation (AF) in type 2 diabetes mellitus (T2DM). However, the molecular mechanisms underlying these processes especially their interactions have not been fully elucidated.<h4>Objective</h4>To explore the potential role of ER stress-mitochondrial oxidative stress in atrial remodeling and AF induction in diabetes.<h4>Methods ...[more]

PMID: 35344886

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Project description:Increasing evidence in substantiating the roles of endoplasmic reticulum stress, oxidative stress, and inflammatory responses and their interplay is evident in various diseases. However, an in-depth mechanistic understanding of the crosstalk between the intracellular stress signaling pathways and inflammatory responses and their participation in disease progression has not yet been explored. Progress has been made in our understanding of the cross talk and integrated stress signaling network between endoplasmic reticulum stress and oxidative stress towards the pathogenesis of diabetic nephropathy. In this present study, we studied the crosstalk between the endoplasmic reticulum stress and oxidative stress by understanding the role of protein disulfide isomerase and endoplasmic reticulum oxidase 1α, a key player in redox protein folding in the endoplasmic reticulum. We had recruited a total of 90 subjects and divided into three groups (control (n = 30), type 2 diabetes mellitus (n = 30), and diabetic nephropathy (n = 30)). We found that endoplasmic reticulum stress markers, activating transcription factor 6, inositol-requiring enzyme 1α, protein kinase RNA-like endoplasmic reticulum kinase, C/EBP homologous protein, and glucose-regulated protein-78; oxidative stress markers, thioredoxin-interacting protein and cytochrome b-245 light chain; and the crosstalk markers, protein disulfide isomerase and endoplasmic reticulum oxidase-1α, were progressively elevated in type 2 diabetes mellitus and diabetic nephropathy subjects. The association between the crosstalk markers showed a positive correlation with endoplasmic reticulum stress and oxidative stress markers. Further, the interplay between endoplasmic reticulum stress and oxidative stress was investigated in vitro using a human leukemic monocytic cell line under a hyperglycemic environment and examined the expression of protein disulfide isomerase and endoplasmic reticulum oxidase-1α. DCFH-DA assay and flow cytometry were performed to detect the production of free radicals. Further, phosphorylation of eIF2α in high glucose-exposed cells was studied using western blot. In conclusion, our results shed light on the crosstalk between endoplasmic reticulum stress and oxidative stress and significantly contribute to the onset and progression of diabetic nephropathy and therefore represent the major therapeutic targets for alleviating micro- and macrovascular complications associated with this metabolic disturbance. Graphical abstract.

Dataset Information

IP3R1/GRP75/VDAC1 complex mediates endoplasmic reticulum stress-mitochondrial oxidative stress in diabetic atrial remodeling.

Rationale

Objective

Methods and results

Conclusions

Publications

IP3R1/GRP75/VDAC1 complex mediates endoplasmic reticulum stress-mitochondrial oxidative stress in diabetic atrial remodeling.

Similar Datasets

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